Chiral 3-(1-amino-1,1-bisalkylmethyl)-1-substituted-pyrrolidines are key intermediates in the synthesis of naphthyridine and quinoline antibacterial agents. Such antibacterial agents have been described, for example, in U.S. Pat. Nos. 5,072,001 and related 5,157,128 for which references are incorporated herein.
In the above mentioned patents, there is a description of the process for the preparation of 3-(1-amino-1,1-bisalkylmethyl)-1-substituted-pyrrolidines. For example, 3-(1-amino-1,1-methylethyl)-1-substituted-pyrrolidines are described as being prepared by a 10-step process from dimethyl itaconate and (S)-1-phenethylamine and include several chromatographic procedures to purify intermediates in the overall synthesis.
The object of the present invention is to provide an alternative and improved economical and high yield method for converting inexpensive L-malic acid or its opposite configuration D-malic acid into chiral 3-(1-amino-1,1-bisalkylmethyl)-1-substituted-pyrrolidines, and, in particular, the L-malic acid into (R)-3-(1-amino-1-methylethyl)-1-substituted-pyrrolidines in six steps.
The new method is actually a 3-step process from the readily available starting materials, the chiral 1-substituted-3-pyrrolidinols. Such economical methods are described in European Patent Application Number 452,143. In particular, (S)-1-benzyl-3-pyrrolidinol as a starting material may be prepared in a high yield form L-malic acid in two steps as described by M. M. Bower Nemia, J. Lee, M. M. Joullie, Syn. Commun., 13, 1117 (1983).
Thus, the object of the present invention is also to provide a simple 3-step process for the preparation of chiral 3-(1-amino-1,1-bisalkylmethyl)-1-substituted-pyrrolidines by first converting the alcohol function of a chiral 1-substituted-3-pyrrolidinol to its mesylate or tosylate derivative. Secondly, displacing with cyanide the tosylate or mesylate group resulting in a chiral compound with inverted configuration, and then dialkylating the cyano group with an alkyl carbanion reagent to give the desired chiral pyrrolidine intermediate without racemization and with retention of configuration. The use of alkyl cerium dichloride reagents such as methyl cerium dichloride has been reported to add to non-chiral and racemic nitriles to give corresponding primary amines, J. E. Ciganek, J. Org. Chem., 57, 4521 (1992). The present invention is the first example of addition of an alkylcarbanion to a chiral nitrile, in which the chiral center is located .alpha. to the activating nitrile group, to give an optically active tertiary amine with retention of optical purity at the .alpha.-carbon site.